Melanin | Wikipedia audio article


Melanin ( (listen); from Greek: μέλας
melas, “black, dark”) is a broad term for a group of natural pigments found in most
organisms. Melanin is produced through a multistage chemical
process known as melanogenesis, where the oxidation of the amino acid tyrosine is followed
by polymerization. The melanin pigments are produced in a specialized
group of cells known as melanocytes. There are three basic types of melanin: eumelanin,
pheomelanin, and neuromelanin. The most common type is eumelanin, of which
there are two types—brown eumelanin and dark brown eumelanin. Pheomelanin is a cysteine-derivative that
contains polybenzothiazine portions that are largely responsible for the color of red hair,
among other pigmentation. Neuromelanin is found in the brain. Research has been undertaken to investigate
its efficacy in treating neurodegenerative disorders such as Parkinson’s.In the human
skin, melanogenesis is initiated by exposure to UV radiation, causing the skin to darken. Melanin is an effective absorbent of light;
the pigment is able to dissipate over 99.9% of absorbed UV radiation. Because of this property, melanin is thought
to protect skin cells from UVB radiation damage, reducing the risk of folate depletion and
dermal degradation, and it is considered that exposure to UV radiation is associated with
increased risk of malignant melanoma, a cancer of melanocytes (melanin cells). Studies have shown a lower incidence for skin
cancer in individuals with more concentrated melanin, i.e. darker skin tone. However, the relationship between skin pigmentation
and photoprotection is still uncertain.==Humans==In humans, melanin is the primary determinant
of skin color. It is also found in hair, the pigmented tissue
underlying the iris of the eye, and the stria vascularis of the inner ear. In the brain, tissues with melanin include
the medulla and pigment-bearing neurons within areas of the brainstem, such as the locus
coeruleus . It also occurs in the zona reticularis of the adrenal gland.The melanin in the skin
is produced by melanocytes, which are found in the basal layer of the epidermis. Although, in general, human beings possess
a similar concentration of melanocytes in their skin, the melanocytes in some individuals
and ethnic groups produce variable amounts of melanin. Some humans have very little or no melanin
synthesis in their bodies, a condition known as albinism.Because melanin is an aggregate
of smaller component molecules, there are many different types of melanin with different
proportions and bonding patterns of these component molecules. Both pheomelanin and eumelanin are found in
human skin and hair, but eumelanin is the most abundant melanin in humans, as well as
the form most likely to be deficient in albinism.===Eumelanin===Eumelanin polymers have long been thought
to comprise numerous cross-linked 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic
acid (DHICA) polymers.There are two types of eumelanin, which are brown eumelanin and
black eumelanin. Those two types of eumelanin chemically differ
from each other in their pattern of polymeric bonds. A small amount of black eumelanin in the absence
of other pigments causes grey hair. A small amount of brown eumelanin in the absence
of other pigments causes yellow (blond) hair. As the body ages, it continues to produce
black eumelanin but stops producing brown eumelanin, resulting in the grey hair that
is common in elderly people.===Pheomelanin===Pheomelanins (or phaeomelanins) impart a pink
to red hue, depending upon the concentration. Pheomelanins are particularly concentrated
in the lips, nipples, glans of the penis, and vagina. When a small amount of brown eumelanin in
hair, which would otherwise cause blond hair, is mixed with red pheomelanin, the result
is orange hair, which is typically called “red” or “ginger” hair. Pheomelanin is also present in the skin, and
redheads consequently often have a more pinkish hue to their skin as well. In chemical terms, pheomelanins differ from
eumelanins in that the oligomer structure incorporates benzothiazine and benzothiazole
units that are produced, instead of DHI and DHICA, when the amino acid L-cysteine is present.====Trichochromes====
Trichochromes (formerly called trichosiderins) are pigments produced from the same metabolic
pathway as the eumelanins and pheomelanins, but unlike those molecules they have low molecular
weight. They occur in some red human hair.===Neuromelanin===Neuromelanin (NM) is a dark insoluble polymer
pigment produced in specific populations of catecholaminergic neurons in the brain. Humans have the largest amount of NM, which
is present in lesser amounts in other primates, and totally absent in many other species. The biological function remains unknown, although
human NM has been shown to efficiently bind transition metals such as iron, as well as
other potentially toxic molecules. Therefore, it may play crucial roles in apoptosis
and the related Parkinson’s disease.==Other organisms==
Melanins have very diverse roles and functions in various organisms. A form of melanin makes up the ink used by
many cephalopods (see cephalopod ink) as a defense mechanism against predators. Melanins also protect microorganisms, such
as bacteria and fungi, against stresses that involve cell damage such as UV radiation from
the sun and reactive oxygen species. Melanin also protects against damage from
high temperatures, chemical stresses (such as heavy metals and oxidizing agents), and
biochemical threats (such as host defenses against invading microbes). Therefore, in many pathogenic microbes (for
example, in Cryptococcus neoformans, a fungus) melanins appear to play important roles in
virulence and pathogenicity by protecting the microbe against immune responses of its
host. In invertebrates, a major aspect of the innate
immune defense system against invading pathogens involves melanin. Within minutes after infection, the microbe
is encapsulated within melanin (melanization), and the generation of free radical byproducts
during the formation of this capsule is thought to aid in killing them. Some types of fungi, called radiotrophic fungi,
appear to be able to use melanin as a photosynthetic pigment that enables them to capture gamma
rays and harness this energy for growth.The darker feathers of birds owe their color to
melanin and are less readily degraded by bacteria than unpigmented ones or those containing
carotenoid pigments. Feathers that contain melanin are also 39%
more resistant to abrasion than those that do not because melanin granules help fill
the space between the keratin strands that form feathers.Melanin is also important in
mammalian pigmentation. The coat pattern of mammals is determined
by the agouti gene which regulates the distribution of melanin. The mechanisms of the gene have been extensively
studied in mice to provide an insight into the diversity of mammalian coat patterns.Melanin
in arthropods has been observed to be deposited in layers thus producing a Bragg reflector
of alternating refractive index. When the scale of this pattern matches the
wavelength of visible light, structural coloration arises: giving a number of species an iridescent
color.Arachnids are one of the few groups in which melanin has not been easily detected,
though researchers found data suggesting spiders do in fact produce melanin.Some moth species,
including the Wood Tiger moth, convert resources to melanin in order to enhance their thermoregulation. As the Wood Tiger moth has populations over
a large range of latitudes, it has been observed that more northern populations showed higher
rates of melanization. In both yellow and white male phenotypes of
the Wood Tiger moth, individuals with more melanin had a heightened ability to trap heat
but an increased predation rate due to a weaker and less effective aposematic signal.===Plants===Melanin produced by plants are sometimes referred
to as ‘catechol melanins’ as they can yield catechol on alkali fusion. It is commonly seen in the enzymatic browning
of fruits such as bananas. Chestnut shell melanin can be used as an antioxidant
and coloring agent. Biosynthesis involves the oxidation of indole-5,6-quinone
by the tyrosinase type polyphenol oxidase from tyrosine and catecholamines leading to
the formation of catechol melanin. Despite this many plants contain compounds
which inhibit the production of melanins.==Biosynthetic pathways==The first step of the biosynthetic pathway
for both eumelanins and pheomelanins is catalysed by tyrosinase. Tyrosine → DOPA → dopaquinoneDopaquinone
can combine with cysteine by two pathways to benzothiazines and pheomelanins Dopaquinone + cysteine → 5-S-cysteinyldopa
→ benzothiazine intermediate → pheomelaninDopaquinone + cysteine → 2-S-cysteinyldopa → benzothiazine
intermediate → pheomelaninAlso, dopaquinone can be converted to leucodopachrome and follow
two more pathways to the eumelanins Dopaquinone → leucodopachrome → dopachrome
→ 5,6-dihydroxyindole-2-carboxylic acid → quinone → eumelaninDopaquinone → leucodopachrome
→ dopachrome → 5,6-dihydroxyindole → quinone → eumelaninDetailed metabolic pathways can
be found in the KEGG database (see External links).==Microscopic appearance==
Melanin is brown, non-refractile, and finely granular with individual granules having a
diameter of less than 800 nanometers. This differentiates melanin from common blood
breakdown pigments, which are larger, chunky, and refractile, and range in color from green
to yellow or red-brown. In heavily pigmented lesions, dense aggregates
of melanin can obscure histologic detail. A dilute solution of potassium permanganate
is an effective melanin bleach.==Genetic disorders and disease states==
There are approximately nine types of oculocutaneous albinism, which is mostly an autosomal recessive
disorder. Certain ethnicities have higher incidences
of different forms. For example, the most common type, called
oculocutaneous albinism type 2 (OCA2), is especially frequent among people of black
African descent. It is an autosomal recessive disorder characterized
by a congenital reduction or absence of melanin pigment in the skin, hair, and eyes. The estimated frequency of OCA2 among African-Americans
is 1 in 10,000, which contrasts with a frequency of 1 in 36,000 in white Americans. In some African nations, the frequency of
the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000. Another form of Albinism, the “yellow oculocutaneous
albinism”, appears to be more prevalent among the Amish, who are of primarily Swiss and
German ancestry. People with this IB variant of the disorder
commonly have white hair and skin at birth, but rapidly develop normal skin pigmentation
in infancy.Ocular albinism affects not only eye pigmentation but visual acuity, as well. People with albinism typically test poorly,
within the 20/60 to 20/400 range. In addition, two forms of albinism, with approximately
1 in 2700 most prevalent among people of Puerto Rican origin, are associated with mortality
beyond melanoma-related deaths. The connection between albinism and deafness
is well known, though poorly understood. In his 1859 treatise On the Origin of Species,
Charles Darwin observed that “cats which are entirely white and have blue eyes are generally
deaf”. In humans, hypopigmentation and deafness occur
together in the rare Waardenburg’s syndrome, predominantly observed among the Hopi in North
America. The incidence of albinism in Hopi Indians
has been estimated as approximately 1 in 200 individuals. Similar patterns of albinism and deafness
have been found in other mammals, including dogs and rodents. However, a lack of melanin per se does not
appear to be directly responsible for deafness associated with hypopigmentation, as most
individuals lacking the enzymes required to synthesize melanin have normal auditory function. Instead the absence of melanocytes in the
stria vascularis of the inner ear results in cochlear impairment, though why this is,
is not fully understood. In Parkinson’s disease, a disorder that affects
neuromotor functioning, there is decreased neuromelanin in the substantia nigra and locus
coeruleus as consequence of specific dropping out of dopaminergic and noradrenergic pigmented
neurons. This results in diminished dopamine and norepinephrine
synthesis. While no correlation between race and the
level of neuromelanin in the substantia nigra has been reported, the significantly lower
incidence of Parkinson’s in blacks than in whites has “prompt[ed] some to suggest that
cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from
external toxins.”In addition to melanin deficiency, the molecular weight of the melanin polymer
may be decreased by various factors such as oxidative stress, exposure to light, perturbation
in its association with melanosomal matrix proteins, changes in pH, or in local concentrations
of metal ions. A decreased molecular weight or a decrease
in the degree of polymerization of ocular melanin has been proposed to turn the normally
anti-oxidant polymer into a pro-oxidant. In its pro-oxidant state, melanin has been
suggested to be involved in the causation and progression of macular degeneration and
melanoma. Rasagiline, an important monotherapy drug
in Parkinson’s disease, has melanin binding properties, and melanoma tumor reducing properties.Higher
eumelanin levels also can be a disadvantage, however, beyond a higher disposition toward
vitamin D deficiency. Dark skin is a complicating factor in the
laser removal of port-wine stains. Effective in treating white skin, in general,
lasers are less successful in removing port-wine stains in people of Asian or African descent. Higher concentrations of melanin in darker-skinned
individuals simply diffuse and absorb the laser radiation, inhibiting light absorption
by the targeted tissue. In similar manner, melanin can complicate
laser treatment of other dermatological conditions in people with darker skin. Freckles and moles are formed where there
is a localized concentration of melanin in the skin. They are highly associated with pale skin. Nicotine has an affinity for melanin-containing
tissues because of its precursor function in melanin synthesis or its irreversible binding
of melanin. This has been suggested to underlie the increased
nicotine dependence and lower smoking cessation rates in darker pigmented individuals.==Human adaptation=====
Physiology===Melanocytes insert granules of melanin into
specialized cellular vesicles called melanosomes. These are then transferred into the keratinocyte
cells of the human epidermis. The melanosomes in each recipient cell accumulate
atop the cell nucleus, where they protect the nuclear DNA from mutations caused by the
ionizing radiation of the sun’s ultraviolet rays. In general, people whose ancestors lived for
long periods in the regions of the globe near the equator have larger quantities of eumelanin
in their skins. This makes their skins brown or black and
protects them against high levels of exposure to the sun, which more frequently result in
melanomas in lighter-skinned people.Not all the effects of pigmentation are advantageous. Pigmentation increases the heat load in hot
climates, and black people absorb 30% more heat from sunlight than do white people, although
this factor may be offset by more profuse sweating. In cold climates black skin entails more heat
loss by radiation. Pigmentation also hinders synthesis of vitamin
D, so that in areas of poor nutrition black children are more liable to rickets than white
children. Since pigmentation appears to be not entirely
advantageous to life in the tropics, other hypotheses about its biological significance
have been advanced, for example a secondary phenomenon induced by adaptation to parasites
and tropical diseases.===Evolutionary origins===
Early humans evolved to have dark skin color around 1.2 million years ago, as an adaptation
to a loss of body hair that increased the effects of UV radiation. Before the development of hairlessness, early
humans had reasonably light skin underneath their fur, similar to that found in other
primates. The most recent scientific evidence indicates
that anatomically modern humans evolved in Africa between 200,000 and 100,000 years,
and then populated the rest of the world through one migration between 80,000 and 50,000 years
ago, in some areas interbreeding with certain archaic human species (Neanderthals, Denisovans,
and possibly others). It seems likely that the first modern humans
had relatively large numbers of eumelanin-producing melanocytes, producing darker skin similar
to the indigenous people of Africa today. As some of these original people migrated
and settled in areas of Asia and Europe, the selective pressure for eumelanin production
decreased in climates where radiation from the sun was less intense. This eventually produced the current range
of human skin color. Of the two common gene variants known to be
associated with pale human skin, Mc1r does not appear to have undergone positive selection,
while SLC24A5 has undergone positive selection.===Effects===
As with peoples having migrated northward, those with light skin migrating toward the
equator acclimatize to the much stronger solar radiation. Most people’s skin darkens when exposed to
UV light, giving them more protection when it is needed. This is the physiological purpose of sun tanning. Dark-skinned people, who produce more skin-protecting
eumelanin, have a greater protection against sunburn and the development of melanoma, a
potentially deadly form of skin cancer, as well as other health problems related to exposure
to strong solar radiation, including the photodegradation of certain vitamins such as riboflavins, carotenoids,
tocopherol, and folate.Melanin in the eyes, in the iris and choroid, helps protect them
from ultraviolet and high-frequency visible light; people with gray, blue, and green eyes
are more at risk for sun-related eye problems. Further, the ocular lens yellows with age,
providing added protection. However, the lens also becomes more rigid
with age, losing most of its accommodation — the ability to change shape to focus from
far to near — a detriment due probably to protein crosslinking caused by UV exposure. Recent research suggests that melanin may
serve a protective role other than photoprotection. Melanin is able to effectively chelate metal
ions through its carboxylate and phenolic hydroxyl groups, in many cases much more efficiently
than the powerful chelating ligand ethylenediaminetetraacetate (EDTA). Thus, it may serve to sequester potentially
toxic metal ions, protecting the rest of the cell. This hypothesis is supported by the fact that
the loss of neuromelanin observed in Parkinson’s disease is accompanied by an increase in iron
levels in the brain.==Physical properties and technological applications
==Evidence exists in support of a highly cross-linked
heteropolymer bound covalently to matrix scaffolding melanoproteins. It has been proposed that the ability of melanin
to act as an antioxidant is directly proportional to its degree of polymerization or molecular
weight. Suboptimal conditions for the effective polymerization
of melanin monomers may lead to formation of lower-molecular-weight, pro-oxidant melanin
that has been implicated in the causation and progression of macular degeneration and
melanoma. Signaling pathways that upregulate melanization
in the retinal pigment epithelium (RPE) also may be implicated in the downregulation of
rod outer segment phagocytosis by the RPE. This phenomenon has been attributed in part
to foveal sparing in macular degeneration.==See also==
Albino Albinism in biology
Griscelli syndrome, a syndrome characterised by hypopigmentation
Human skin color Melanin theory
Melanism Melanogenesis, melanin production
Risks and benefits of sun exposure Vitamin D
Skin whitening Ferulic acid

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